This application represents an interdisciplinary effort to characterize the etiopathologic bases of the diabetes syndrome in non-obese diabetic (NOD) mice. These mice spontaneously develop a diabetes syndrome resembling autoimmune-associated type I diabetes mellitus in humans. The nature and number of genes underlying diabetogenesis in NOD mice will be analyzed by outcrosses onto diabetes-susceptible inbred strain genetic backgrounds. The pathogenic significance of major histocompatibility complex genes and of endogenous beta cell retroviruses will be assessed. The physiopathological basis for the sexually dimorphic expression of diabetes in NOD mice (75% incidence in female versus 29% in males) will be established by a combined endocrinologic and immunologic comparison of males and females. Since insulitis and production of autoantibodies against pancreatic islets are the salient pathologic indicators of the pre-diabetic state in NOD mice, their immunologic functions will be carefully compared to the diabetes-resistant non-obese normal (NON) substrain. The relationship between autoimmunity, islet autoantigens, and beta cell destruction will be explored. Age-associated histopathological changes in other tissues and organs will be established. The proposed studies employing manipulation of the immune system should allow an understanding of how defects in immunoregulation in a diabetes-susceptible genotype can trigger pathogenetic sequelae leading to overt diabetes.